The present invention relates to pharmaceutical compositions, and particularly pharmaceutical compositions incorporating compounds that affect cytokine production and/or secretion. The present invention also relates to methods for treating a wide variety of conditions, diseases and disorders, and particularly those associated with dysfunction of cytokine production and/or secretion. Of particular interest are pharmaceutical compositions useful for preventing and treating conditions, diseases and disorders associated with undesirably high levels of cytokine production and/or secretion.
Cytokines are polypeptides that affect cell function and modulate interactions between cells associated with immune, inflammatory or hematopoietic responses. Cytokines include monokines (which are generally produced and secreted by mononuclear cells, such as macrophages and monocytes) and lymphokines (which are generally produced and secreted by lymphocytes). Examples of cytokines include interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor (TNF, which includes TNF-alpha and TNF-beta). Cytokines have been recognized as having numerous functions, particularly with regards to immune system and inflammatory responses. See, Ebadi et al., Neurochem. Int., 30(4-5): 347-374 (1997).
However, excessive or unregulated cytokine production and secretion has been implicated in mediating or exacerbating various diseases and disorders, particularly those associated with deficiencies in immunoregulation and physiological conditions (e.g., inflammation). See, for example, Tamaka, Jap. J. Clin. Med., 56(1): 97-101 (1998); Dinarello, J. Biol. Regul. Homeostat. Ag., 11(3): 91-103 (1997); Moldawer et al., Sem. Oncol., 25(1): 73-81 (1998); Balkwill, J. Viral Hepat., 4(2): 6-15 (1997); Martin et al., Eur. Resp. J., 10(9): 2139-2146 (1997) and PCT WO 98/25619. For example, pro-inflammatory cytokines are produced by a variety of cell types, play major roles in the regulation of host immune responses, and have been implicated in diverse pathologies. Exemplary pro-inflammatory cytokines include interleukin species, prostaglandin species, colony stimulating factor and tumor necrosis factor.
Cytokines mediate a wide range of symptoms associated with trauma and infection, such as fever, anorexia, tissue wasting (cachexia), acute phase protein production and immunomodulation. In part, such symptoms result form a coordinated response, in which the immune system is activated and biochemical actions occur. Although the cytokine mediated response is an essential part of the response to trauma and infection, excessive production of cytokines, or production of cytokines in an inappropriate biological context, are associated with mortality and pathology in a wide range of diseases. Exemplary diseases and disorders associated with excessive or unregulated cytokine production and/or secretion include malaria, sepsis, rheumatoid arthritis, inflammatory bowel disease, cancer and AIDS. See, for example, Grimble et al., Zeitschrift fur Ernahrungswissenschaft, 37(1): 57-65 (1998). See also, Barnes, Int. J. Biochem. Cell Biol., 29(6): 867-870 (1997).
Nicotine has been proposed to have a number of pharmacological effects. For a discussion of reported pharmacological effects of nicotine, see U.S. Pat. No. 5,663,356 to Ruecroft et al. at col. 1, line 39 through col. 2, line 8. In addition, various nicotinic compounds have been reported as being useful for treating a wide variety of conditions and disorders. See, for example, Williams et al. DNandP 7(4):205-227 (1994), Arneric et al., CNS Drug Rev. 1(1):1-26 (1995), Arneric et al., Exp. Opin. Invest. Drugs 5(1): 79-100 (1996), Bencherif et al., JPET 279:1413-1421 (1996), Lippiello et al., JPET 279:1422-1429 (1996), Damaj et al., Neuroscience (1997), Holladay et al., J. Med. Chem 40(28): 4169-4194 (1997), Bannon et al., Science 279: 77-80 (1998), PCT WO 94/08992, PCT WO 97/19059, and U.S. Pat. No. 5,278,176 to Lin, U.S. Pat. No. 5,583,140 to Bencherif et al., U.S. Pat. No. 5,597,919 to Dull et al., U.S. Pat. No. 5,616,716 to Dull et al., U.S. Pat. No. 5,811,442 to Bencherif et al. and U.S. Pat. No. 5,852,041 to Cosford et al., and U.S. patent application Ser. No. 09/054,130.
Nicotine has been proposed as a treatment for inflammatory bowel disease, such as ulcerative colitis. See, for example, Lashner et al., Digestive Diseases and Sciences, 35(7): 827-832 (1990); Pullan et al., N. Engl. J. Med., 330: 811-815 (1994); and Sanborn et al., Aliment Pharmacol. Ther., 11: 663-671 (1997). See, also, Silverstein et al., Mayo Clin. Proc., 69: 425-429 (1994) and Birtwistle, Postgrad. Med. J., 72: 714-718 (1996); as well as the results of studies reported by Zijistra et al., Gut, 35: 247-251 (1994) and Pullan, Ann. R. Coll. Surg. Eng., 78: 85-91 (1996). In addition, administration of nicotinic compounds has been suggested as useful in the prevention and treatment of inflammatory bowel disease. See, for example, U.S. Pat. No. 5,604,231 to Smith et al.
The existence of interaction between nicotinic processes and the immune system has been proposed. See, for example, Lukas et al., Intl. Rev. Neurobiol., Vol. 34, pp. 25-130 (1992) and Jonakait, TINS, Vol. 16 (10), pp. 419-423 (1993). The administration of nicotine has been shown to elicit inhibition of IL-2 production. See, for example, Denicoff et al., Ann. Intern. Med., Vol.107, pp. 293-300 (1987); Plata-Salaman et al., Neurosc. Biobeh. Res., Vol. 15, pp.185-215 (1991) and Hanish et al., J. Neurosc., Vol. 13, pp. 3368-3374 (1993). Nicotine has been reported to exhibit effects upon cytokine production. Zhang et al., Int. J. Immunopharmacol., 18(8-9): 467-478 (1996). For example, nicotine has been reported to have an effect upon human gingival fibroblast reproduction. Peacock et al., J. Periodtol, 64(7): 658-665 (1 993). It also has been reported that nicotine has an observed inhibitory effect upon prostaglandins in an inverse dose dependent manner (i.e., with greatest inhibition in relation to the lowest dose). Zijlstra et al., Gut, 35: 247-251 (1994). In addition, nicotine has been reported to have an inhibitory effect upon T-helper 2 (TH2) cell function as determined by inhibition of IL-10 production. Madretsma et al., Eur. J. Gastroen Hepat., 8(10): 1017-1020 (1996). Furthermore, it has been reported that nicotine exhibits immunoregulatory effects through modulation of cytokine production, as evidenced by an observed inhibition of IL-2 and TNF-alpha. Madretsma et al., Immunopharmacology, 35: 47-51 (1996). See, also, Van Dijk et al., European Journal of Pharmacology, 278(1): R11-2 (1995).
It has been reported that it would be desirable to control the undesirable effects exhibited by inflammatory mediators, such as cytokines. Sartor, Amer. J. Gastroent., 92(12): S5-S11 (1997); Wallace et al.,Proc. Soc. Exp. Biol. Med., 214(3): 192-203 (1997) and Matthys et al., Nutrition, 13(9): 763-770 (1997).
Thus, it would be desirable to provide a pharmaceutical composition useful for the prevention and treatment of conditions, diseases or disorders where inhibition of the production and/or secretion of specific cytokines is desired. It would be highly beneficial to provide individuals suffering from certain conditions, diseases or disorders with interruption of the symptoms associated therewith by the administration of a pharmaceutical composition that has a beneficial effect upon the production and secretion of cytokines. It also would be highly beneficial that such pharmaceutical composition not provide any significant associated side effects attendant with interaction of that composition with cardiovascular sites (e.g., increased heart rate and blood pressure) or at skeletal muscle sites.
The present invention relates to a method for providing or treating a wide variety of conditions, diseases and disorders, and particularly those associated with dysfunction of cytokine production and/or secretion. In particular, the present invention relates to a method for providing prevention or treatment of conditions associated with an alteration in normal cytokine production and/or secretion (e.g., undesirably high levels of cytokine production and/or secretion). The method involves administering to a patient an effective amount of a compound of the present invention. Compounds of the present invention include aryl substituted olefinic amine compounds, pyridyloxyalkylamines and phenoxyalkylamines, and aryl substituted amine compounds, such as 3-aminophenyl amine compounds. The method also involves administering pro-drug derivatives of compounds of the present invention.
The present invention, in another aspect, relates to a pharmaceutical composition comprising an effective amount of a compound of the present invention. Such a pharmaceutical composition incorporates a compound which, when employed in effective amounts, has the capability of affecting dysfunction associated with cytokine production and/or secretion, and hence has the capability of acting as a therapeutic agent for the prevention or treatment of those conditions associated with abnormal cytokine production and/or secretion. Those compositions also can include pro-drug derivatives of compounds of the present invention.
The pharmaceutical compositions of the present invention are useful for the prevention or treatment of conditions associated with dysfunction of cytokine production and/or secretion. In particular, the pharmaceutical compositions are useful in inhibiting cytokine production and/or secretion. The pharmaceutical compositions provide therapeutic benefit to individuals suffering from such conditions and exhibiting clinical manifestations of such disorders in that the compounds within those compositions have the potential to (i) prevent and/or suppress the production and/or secretion of cytokines, and (ii) not provide appreciable adverse side effects (e.g., significant increases in blood pressure and heart rate, and significant effects upon skeletal muscle). The pharmaceutical compositions of the present invention are believed to be safe and effective with regards to prevention and treatment of conditions associated with dysfunction of cytokine production and/or secretion.